Parkinson disease (PD) is a progressive neurodegenerative condition causing serious motor and non-motor disability over time. Falls are common in PD and represent the most severe motor disability. Although nigrostriatal dopaminergic denervation has been recognized as a key pathobiological mechanism, there is general consensus that the majority of postural control and gait impairments associated with falls in PD are resistant to dopaminergic treatment. Therefore, there is a need to further explore non-dopaminergic mechanisms of gait control in PD. Recent neuropathological studies show that PD is a multi-system neurodegeneration syndrome that also affects multiple non-dopaminergic transmitters. For example, the pedunculopontine nucleus (PPN), a brainstem locomotor center, also degenerates in PD and PPN dysfunction has been associated with dopamine-resistant akinesia. The PPN has cholinergic and non-cholinergic neurons and provides the major cholinergic input to the thalamus. Preliminary results from our current RR&D project B4213R suggest that cholinergic denervation, especially of the thalamus, rather than the degree of nigrostriatal dopaminergic denervation is associated with falls in PD. Apart from primary neuronal dopaminergic and non- dopaminergic degeneration, general cortical dysfunction, especially of the frontal lobe, may affect gait control in PD. Furthermore, the presence of common age-associated factors, such as brain small vessel disease (BSVD) may also affect mobility functions in PD. BSVD is also more common in patients with PD likely due to their more sedentary lifestyle, and has been found to independently contribute to higher fall risk. The presence of BSVD is associated with reduced cortical perfusion and may affect cortical neurotransmitter functions non- selectively. Therefore, a critical challenge in multi-system neurodegeneration and aging is how to implicate a specific system in the pathophysiology of symptoms when other systems simultaneously decline. Longitudinal study designs have a particular advantage in the study of neurodegenerative disorders and aging as they allow a unique within-subject analysis of interval changes of multiple variables over time and relate them to baseline functions. Therefore, the overarching goal of the current proposal is to repeat brain MRI, global cortical cerebral blood flow (CBF, derived from dynamic PET imaging), dopaminergic and cholinergic PET imaging, clinical, mobility, functional and cognitive assessments in project B4213R participants at their 3.5-year anniversary of their enrollment in the study. Cortical CBF data extracted from the dynamic PET imaging set will enable global assessment of cortical function to study global cortical factors involved in gait control. The CBF data will also allow analysis of effects of global cortical function on mobility versus possible specific transmitter effects, if present. In addition, we propose to perform GABAergic PET imaging using the [C-11]Flumazenil radioligand in a subset of patients to determine if possible thalamic effects on mobility are specific for thalamic cholinergic denervation or represent global thalamic dysfunction. PUBLIC HEALTH RELEVANCE: Narrative. Costs of Parkinson disease and associated morbidity are an increasing source of expense for the VA because of the disproportionately elderly population of veterans. Improved insights in postural and gait functions are, therefore, directly relevant to the diagnosis and preventive care of elderly veterans with PD. The proposed study will allow prognostic assessment to identify risk factors for gait and balance problems such as falls, in veterans with Parkinson disease. The project will apply imaging techniques of brain magnetic resonance imaging (MRI) and positron emission tomography (PET) to study anatomic and chemical changes in the brain, including information on global brain blood flow, specific neurotransmitters such as dopamine, acetylcholine, and GABA, and small vessel disease. Identification of the key mechanism that is most contributory to the development of mobility disability in PD will allow more precise targeting of future therapeutic interventions.